TNF and Plasmodium berghei ANKA-induced cerebral malaria.
The cerebral pathology observed in Plasmodium berghei ANKA-infected CBA mice has been attributed to overproduction of TNF, the mice in which this syndrome is seen being those with the highest serum TNF levels. To investigate this further, we injected recombinant human TNF into malaria-primed mice to see if we could reproduce the cerebral changes observed in P. berghei ANKA infections. A range of doses, administered as a single or repeated injections, or via osmotic pumps, failed to reproduce these changes, but did induce hypoglycaemia, midzonal liver necrosis and neutrophil adhesion in pulmonary vessels. This pathology is seen in terminal Plasmodium vinckei infections, but absent in terminal P. berghei ANKA. In addition, the permeability of the blood-brain barrier to Evan's blue, which is present in P. berghei ANKA but not in normal or P. vinckei-infected mice, was not induced by exogenous TNF. Serum levels of TNF were measured in an ELISA assay, and found to be consistently higher in P. vinckei rather than P. berghei ANKA terminal infections. This is consistent with the pathological changes we could reproduce by injecting TNF. For these reasons we suggest that the cerebral pathology seen in mice infected with P. berghei ANKA may be governed by TNF produced locally by monocytes sequestered within the cerebral blood vessels, not simply by systemic levels of this cytokine.
Clark
I A
IA
Zoology Department, John Curtin School of Medical Research, Australian National University, Canberra.
Ilschner
S
S
MacMicking
J D
JD
Cowden
W B
WB
D000818:Animals; D001812:Blood-Brain Barrier; D001927:Brain Diseases / Q000097:blood / Q000276:immunology / Q000469:parasitology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D008288:Malaria / Q000097:blood / Q000150:complications* / Q000276:immunology*; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D010962:Plasmodium berghei / Q000276:immunology*; D011994:Recombinant Proteins / Q000008:administration & dosage; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000378:metabolism / Q000502:physiology*
D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha